Alessandro Amore

The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification

IgA nephropathy is the most common glomerular disease worldwide, yet there is no international consensus for its pathological or clinical classification. Here a new classification for IgA nephropathy is presented by an international consensus working group. The goal of this new system was to identify specific pathological features that more accurately predict risk of progression of renal disease in IgA nephropathy, thus enabling both clinicians and pathologists to improve individual patient prognostication. In a retrospective analysis, sequential clinical data were obtained on 265 adults and children with IgA nephropathy who were followed for a median of 5 years. Renal biopsies from all patients were scored by pathologists blinded to the clinical data for pathological variables identified as reproducible by an iterative process. Four of these variables: (1) the mesangial hypercellularity score, (2) segmental glomerulosclerosis, (3) endocapillary hypercellularity, and (4) tubular atrophy/interstitial fibrosis were subsequently shown to have independent value in predicting renal outcome. These specific pathological features withstood rigorous statistical analysis even after taking into account all clinical indicators available at the time of biopsy as well as during follow-up. The features have prognostic significance and we recommended they be taken into account for predicting outcome independent of the clinical features both at the time of presentation and during follow-up. The value of crescents was not addressed due to their low prevalence in the enrolled cohort.

The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility

Pathological classifications in current use for the assessment of glomerular disease have been typically opinion-based and built on the expert assumptions of renal pathologists about lesions historically thought to be relevant to prognosis. Here we develop a unique approach for the pathological classification of a glomerular disease, IgA nephropathy, in which renal pathologists first undertook extensive iterative work to define pathologic variables with acceptable inter-observer reproducibility. Where groups of such features closely correlated, variables were further selected on the basis of least susceptibility to sampling error and ease of scoring in routine practice. This process identified six pathologic variables that could then be used to interrogate prognostic significance independent of the clinical data in IgA nephropathy (described in the accompanying article). These variables were (1) mesangial cellularity score; percentage of glomeruli showing (2) segmental sclerosis, (3) endocapillary hypercellularity, or (4) cellular/fibrocellular crescents; (5) percentage of interstitial fibrosis/tubular atrophy; and finally (6) arteriosclerosis score. Results for interobserver reproducibility of individual pathological features are likely applicable to other glomerulonephritides, but it is not known if the correlations between variables depend on the specific type of glomerular pathobiology. Variables identified in this study withstood rigorous pathology review and statistical testing and we recommend that they become a necessary part of pathology reports for IgA nephropathy. Our methodology, translating a strong evidence-based dataset into a working format, is a model for developing classifications of other types of renal disease.

Genome-wide association study identifies susceptibility loci for IgA nephropathy

We carried out a genome-wide association study of IgA nephropathy, a major cause of kidney failure worldwide. We studied 1,194 cases and 902 controls of Chinese Han ancestry, with targeted follow up in Chinese and European cohorts comprising 1,950 cases and 1,920 controls. We identified three independent loci in the major histocompatibility complex, as well as a common deletion of CFHR1 and CFHR3 at chromosome 1q32 and a locus at chromosome 22q12 that each surpassed genome-wide significance (P values for association between 1.59 × 10−26 and 4.84 × 10−9 and minor allele odds ratios of 0.63–0.80). These five loci explain 4–7% of the disease variance and up to a tenfold variation in interindividual risk. Many of the alleles that protect against IgA nephropathy impart increased risk for other autoimmune or infectious diseases, and IgA nephropathy risk allele frequencies closely parallel the variation in disease prevalence among Asian, European and African populations, suggesting complex selective pressures.

IgACE: A Placebo-Controlled, Randomized Trial of Angiotensin-Converting Enzyme Inhibitors in Children and Young People with IgA Nephropathy and Moderate Proteinuria

This European Community Biomedicine and Health Research-supported, multicenter, randomized, placebo-controlled, double-blind trial investigated the effect of an angiotensin-converting enzyme inhibitor (ACE-I) in children and young people with IgA nephropathy (IgAN), moderate proteinuria (>1 and <3.5 g/d per 1.73 m(2)) and creatinine clearance (CrCl) >50 ml/min per 1.73 m(2). Sixty-six patients who were 20.5 yr of age (range 9 to 35 yr), were randomly assigned to Benazepril 0.2 mg/kg per d (ACE-I) or placebo and were followed for a median of 38 mo. The primary outcome was the progression of kidney disease, defined as >30% decrease of CrCl; secondary outcomes were (1) a composite end point of >30% decrease of CrCl or worsening of proteinuria until > or =3.5 g/d per 1.73 m(2) and (2) proteinuria partial remission (<0.5 g/d per 1.73 m(2)) or total remission (<160 mg/d per 1.73 m(2)) for >6 mo. Analysis was by intention to treat. A single patient (3.1%) in the ACE-I group and five (14.7%) in the placebo group showed a worsening of CrCl >30%. The composite end point of >30% decrease of CrCl or worsening of proteinuria until nephrotic range was reached by one (3.1%) of 32 patients in the ACE-I group, and nine (26.5%) of 34 in the placebo group; the difference was significant (log-rank P = 0.035). A stable, partial remission of proteinuria was observed in 13 (40.6%) of 32 patients in the ACE-I group versus three (8.8%) of 34 in the placebo group (log-rank P = 0.033), with total remission in 12.5% of ACE-I-treated patients and in none in the placebo group (log-rank P = 0.029). The multivariate Cox analysis showed that treatment with ACE-I was the independent predictor of prognosis; no influence on the composite end point was found for gender, age, baseline CrCl, systolic or diastolic BP, mean arterial pressure, or proteinuria.

Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens

We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry. We identified six new genome-wide significant associations, four in ITGAM-ITGAX, VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA. We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geospatial distribution of risk alleles is highly suggestive of multi-locus adaptation, and genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host–intestinal pathogen interactions in shaping the genetic landscape of IgAN.

Validation of the Oxford classification of IgA nephropathy in cohorts with different presentations and treatments

The Oxford Classification of IgA Nephropathy (IgAN) identified mesangial hypercellularity (M), endocapillary proliferation (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T) as independent predictors of outcome. Whether it applies to individuals excluded from the original study and how therapy influences the predictive value of pathology remain uncertain. The VALIGA study examined 1147 patients from 13 European countries that encompassed the whole spectrum of IgAN. Over a median follow-up of 4.7 years, 86% received renin–angiotensin system blockade and 42% glucocorticoid/immunosuppressive drugs. M, S, and T lesions independently predicted the loss of estimated glomerular filtration rate (eGFR) and a lower renal survival. Their value was also assessed in patients not represented in the Oxford cohort. In individuals with eGFR less than 30 ml/min per 1.73 m2, the M and T lesions independently predicted a poor survival. In those with proteinuria under 0.5 g/day, both M and E lesions were associated with a rise in proteinuria to 1 or 2 g/day or more. The addition of M, S, and T lesions to clinical variables significantly enhanced the ability to predict progression only in those who did not receive immunosuppression (net reclassification index 11.5%). The VALIGA study provides a validation of the Oxford classification in a large European cohort of IgAN patients across the whole spectrum of the disease. The independent predictive value of pathology MEST score is reduced by glucocorticoid/immunosuppressive therapy.

The Oxford IgA nephropathy clinicopathological classification is valid for children as well as adults

To study the predictive value of biopsy lesions in IgA nephropathy in a range of patient ages we retrospectively analyzed the cohort that was used to derive a new classification system for IgA nephropathy. A total of 206 adults and 59 children with proteinuria over 0.5 g/24 h/1.73 m(2) and an eGFR of stage-3 or better were followed for a median of 69 months. At the time of biopsy, compared with adults children had a more frequent history of macroscopic hematuria, lower adjusted blood pressure, and higher eGFR but similar proteinuria. Although their outcome was similar to that of adults, children had received more immunosuppressants and achieved a lower follow-up proteinuria. Renal biopsies were scored for variables identified by an iterative process as reproducible and independent of other lesions. Compared with adults, children had significantly more mesangial and endocapillary hypercellularity, and less segmental glomerulosclerosis and tubulointerstitial damage, the four variables previously identified to predict outcome independent of clinical assessment. Despite these differences, our study found that the cross-sectional correlation between pathology and proteinuria was similar in adults and children. The predictive value of each specific lesion on the rate of decline of renal function or renal survival in IgA nephropathy was not different between children and adults.

Oxidative Stress and Galactose-Deficient IgA1 as Markers of Progression in IgA Nephropathy

BACKGROUND AND OBJECTIVES We assessed the activation of the oxidative stress pathway in patients with IgA nephropathy (IgAN), while evaluating the classic marker of the disease (galactose-deficient serum IgA1). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Sera from 292 patients and 69 healthy controls from Italy and the United States were assayed for advanced oxidation protein products (AOPPs), free sulfhydryl groups on albumin (SH-Alb), and IgA1 with galactose-deficient hinge-region O-glycans (Gd-IgA1). Gd-IgA1 was detected by binding to Helix aspersa agglutinin (HAA) and expressed as total Gd-IgA1 or as degree of galactose deficiency relative to a standard Gd-IgA1 myeloma protein (%HAA). RESULTS Sera from IgAN patients showed higher levels of Gd-IgA1, %HAA, and AOPPs, but lower levels of SH-Alb in comparison to that from healthy controls. Serum levels of AOPPs significantly correlated with serum Gd-IgA1 and %HAA. The relationship between these biomarkers and clinical features at sampling and during follow-up was assessed in 62 patients with long-term follow-up. AOPPs and %HAA correlated with proteinuria at sampling and independently associated with subsequent proteinuria. Levels of AOPPs correlated with rate of decline in renal function after sampling. The combination of a high level of AOPPs and a high level of %HAA associated with decline in estimated GFR. CONCLUSIONS Serum levels of aberrantly glycosylated IgA1 are elevated and oxidative stress pathways are activated in patients with IgAN; the intensity of the stress correlated with expression and progression of the disease. We speculate that oxidative stress may modulate the nephrotoxicity of aberrantly glycosylated IgA1 in IgAN.

Toll‐like receptor 4 expression is increased in circulating mononuclear cells of patients with immunoglobulin A nephropathy

We investigated Toll‐like receptors (TLR‐3, ‐4 and ‐7) expression in circulating mononuclear cells of patients with immunoglobulin A nephropathy (IgAN), a disease with debated relationships with mucosal immunity. TLR‐4 expression (detected by fluorescence activated cell sorter) and mRNA transcriptional levels (Taqman) were significantly higher in patients with IgAN than in healthy controls (P = 0·00200 and P = 0·0200). TLR‐3 and TLR‐7 were not modified significantly. In IgAN patients proteinuria was correlated significantly with TLR‐4 expression (P = 0·0312). In a group of nephrotic syndromes, TLR‐3, ‐4 and ‐7 expression was similar to healthy controls. A significant difference in TLR‐4 expression and mRNA levels was found between very active IgAN patients (proteinuria > 1 g/1·73 m2/day in association with severe microscopic haematuria) and inactive patients (proteinuria < 0·5 g/1·73 m2/day, with absent or minimal haematuria). No correlation with levels of aberrantly glycosylated IgA1, age, renal biopsy features or therapy was found. This study shows for the first time an up‐regulation of TLR‐4 in circulating mononuclear cells of patients with IgAN, particularly in association with proteinuria and heavy microscopic haematuria.

Angiotensin II Local Hyperreactivity in the Progression of IgA Nephropathy

Immunologic and hemodynamic factors are likely to work in synergism in the progression of immunoglobulin A nephropathy (IgAN) toward sclerosis. The local activation of the renin-angiotensin system may be one the most relevant mechanisms. We investigated the hemodynamic effects of the acute administration of angiotensin-converting enzyme inhibitor (ACEI) (captopril 50 mg). The glomerular filtration rate (GFR) and the effective renal plasma flow (ERPF) were measured by 51Cr-EDTA and 125I hippurate clearances. The correspondent filtration fractions (FFs) in basal conditions and after administration of ACEI were calculated, then the changes in FF (delta FF and % delta FF) were determined. We studied 27 IgAN patients. Eighteen patients had normal renal function (GFR, 112 +/- 19 mL/min/1.73 m2) and nine had moderate renal impairment (GFR, 54 +/- 13 mL/min/1.73 m2). Sixteen patients had proteinuria > or = 0.5 g/d. In addition, 12 glomerulonephritis control cases and eight healthy subjects were investigated. After the administration of ACEI in healthy subjects we observed slight modifications in the GFR, a significant increase in the ERPF (P < 0.005), and a significant decrease in FF (P < 0.04). Similarly, in IgAN patients with normal renal function the GFR increased slightly, the ERPF increased significantly (P < 0.01), and there was a decrease in FF (P < 0.01). The delta FF and % delta FF values were not significantly different from those found in the controls. In patients with initial renal failure GFR remained unchanged, ERPF increased significantly (P < 0.005), and FF significantly decreased (P < 0.004). However, the changes in delta FF and % delta FF were significantly greater than those found in healthy controls (P < 0.01) and in IgAN patients with normal renal function (P < 0.001). IgAN patients with proteinuria levels > or = 0.5 g/d showed greater changes in delta FF and % delta FF after the administration of ACEI than patients with proteinuria levels lower than 0.5 g/d (P < 0.003 and P < 0.04, respectively) or proteinuric control cases (P < 0.05 and P < 0.01, respectively). This different response in proteinuric and nonproteinuric patients was evident even when the analysis was limited to the subgroup of IgAN patients with normal renal function. The decrease in FF consequent to an increase in the ERPF after the administration of ACEI suggests a local hyperactivity of the renin-angiotensin system in some cases of IgAN.(ABSTRACT TRUNCATED AT 400 WORDS)